1. Field of the Invention
The present invention relates generally to the field of immunology. More specifically, the present invention relates to the uses of soluble immune response suppressor (SIRS) in the treatment of multiple sclerosis or other autoimmune diseases.
2. Description of the Related Art
Supernatant fluids from murine spleen cell cultures incubated with concanavalin A for 48 hours contain a factor, soluble immune response suppressor (SIRS), which suppressed plaque-forming cell responses to sheep erythrocytes in vitro (Tadakuma et al., 1976). Soluble immune response suppressor is non-dialyzable destroyed by high temperatures, pH 2, trypsin, chymotrypsin and absorbed by spleen and thymus which is suggestive of a glycoprotein. Supernatant fluids with the soluble immune response suppressor activity contained macrophage migration inhibitory factor (MIF). The cellular site of action of the soluble immune response suppressor appeared to be the macrophage (Tadakuma et al., 1976; Aune et al., 1981). Exposure of splenic or peritoneal exudate macrophages to soluble immune response suppressor suppressed antibody responses by untreated splenic lymphoid cells, whereas exposure of splenic lymphoid cells to soluble immune response suppressor was without effect.
Animal modeling using the soluble immune response suppressor also showed anti-autoimmune effects. Young NZB/W mice treated with injections of soluble immune response suppressor of supernatant from mouse spleen cells exposed to concanavalin A showed decreased immunoglobin levels, less antibody to cell nuclei, less proteinuria and less renal pathology as compared with NZB/W mice receiving a control preparation. Soluble immune response suppressor administration beginning at an early age appears to be an effective therapy of the autoimmune disorder in NZB/W mice (Krakauer et al., 1977).
A comparable soluble immune response suppressor system also appears to function in humans. Human polyclonal plaque-forming cell responses by concanavalin A, leukocyte interferon or by suppressor cells activated by these agents is preventable by levamisole, ascorbic acid, catalase, or 2-mercaptoethanol, agents known to interfere with murine soluble immune response suppressor activity. Furthermore, concanavalin A, immune interferon, and leukocyte interferon induced T lymphocytes releases proteins which suppressed immune responses.
Peripheral blood mononuclear cells and OKT8 positive T suppressor cells incubated with human IFN-α decreased pokeweed mitogen-stimulated polyclonal immunoglobin production and inhibited proliferation in mixed lymphocyte cultures. Suppression mediated by these cells was prevented by catalase, ascorbic acid, and 2-mercaptoethanol. These results suggest that IFN-α activated suppressor T cells in human peripheral blood mononuclear cell cultures have certain similarities to IFN-β or to concanavalin A-activated murine suppressor T cells (Schnaper et al., 1983). The similarities between these human suppressor factors and murine soluble immune response suppressor show the existence of a human soluble immune response suppressor pathway. (Schnaper et al., 1984)
Soluble immune response suppressor appears to be a generalized immunomodulatory molecule. IL-1-induced leukocytosis was inhibited or blocked in a dose-dependent manner by soluble immune response suppressor when administered intravenously to CBA mice. An antipyric activity of soluble immune response suppressor was observed in rabbits injected intravenously with lipopolysaccharide (LPS) (Zimecki et al., 1990). Soluble immune response suppressor given intravenously in one or two doses markedly reduced LPS-induced fever. Soluble immune response suppressor is a selective inhibitor of IL-1 activity with respect to T and B cells, rendering them unresponsive to IL-1 activation and/or maturation signals without reversing inhibition of autologous rosette formation induced by factors such as IL-4.
Chronic schistosomiasis mansoni is a helminthic infection characterized by cell-mediated anti-egg granulomatous reactions and a variety of associated immunoregulatory phenomena. There is a strong association between the presence of the soluble immune response suppressor in the serum, the production of the soluble immune response suppressor by intact lesions, and the chronic, immunomodulated stage of schistosomiasis mansoni. The presence of urinary soluble immune response suppressor suggest a possible role for soluble immune response suppressor in the suppressed immune responses often found in nephrotic syndrome with a striking correlation between detection of soluble immune response suppressor and the presence of steroid-responsive nephrotic syndrome.
Delayed Type Hypersensivity (DTH) responses to footpad injection of sheep red blood cells (SRBC) also was inhibited by soluble immune response suppressor. The action of putative regulatory cells to mixed lymphocyte cultures was blocked by antiserum to the N-terminal sequence of soluble immune response suppressor. Mice immunized with alloantigen developed two populations of suppressor cells, one of which is antigen nonspecific and inhibitable by anti-soluble immune response antigen nonspecific and inhibitable by anti-soluble immune response suppressor. Soluble immune response suppressor or soluble immune response suppressor-like proteins are produced during various diseases associated with suppressed immune responsiveness including acquired immune deficiency syndrome, schistosomiasis, and nephrotic syndrome. These data suggest that soluble immune response suppressor may have an important physiological role in regulating immune responses and cell division in general (Aune et al., 1982; Aune et al, 1985; Schnaper et al., 1985).
Three biologically active species of soluble immune response suppressor (SIRS) have been isolated at pH7, pH6, and pH5, SIRS-a7, SIRS-a6, and SIRS-a5, respectively, with nearly identical molecular weights of 11,000, when subjected to molecular sieve chromatography. The molecular basis for these isoforms is not clear yet, but it is consistent with earlier studies showing two separate messenger RNA species coding for soluble immune response suppressor (Webb et al., 1985). Soluble immune response suppressor requires a divalent metal ion, probably ferrous iron, for activity, suggesting that soluble immune response suppressor is also a metalloprotein (Schnaper et al, 1989).
Although the complete sequence of soluble immune response suppressor protein is not known, a putative N-terminal 21 amino acid sequence has been obtained for one of the less hydrophobic isoforms, soluble immune response suppressor-a7 (SIRS-a7). The sequence of SIRS-a7 is unique in mammals, but shows a remarkable homology to the family of short neurotoxins, e.g., short neurotoxin 1, found in sea snake, adder, and cobra species. A synthetic polypeptide based on the 21-residue sequence was also prepared and coupled to thyroglobulin or keyhole limpet hemocyanin to prepare rabbit antisera that neutralizes soluble immune response suppressor bioactivity and precipitate soluble immune response suppressor (Webb et al., 1990). Antisera specific for this sequence blocks the suppressive activity of Con A- or IFN-activated suppressor cells (Devens et al., 1988).
There is no conclusive indication from the prior art that soluble immune response suppressor or the putative N-terminal peptide or any variant thereof has therapeutic properties against multiple sclerosis or other autoimmune diseases. Specifically, the prior art is deficient in methods of using soluble immune response suppressor or the N-terminal peptide or any variant thereof as a therapeutic immunomodulator of multiple sclerosis or other autoimmune diseases. The present invention fulfills this long-standing need and desire in the art.